JP2004517944A - Method for preparing pantoprazole and intermediates thereof - Google Patents
Method for preparing pantoprazole and intermediates thereof Download PDFInfo
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- JP2004517944A JP2004517944A JP2002561459A JP2002561459A JP2004517944A JP 2004517944 A JP2004517944 A JP 2004517944A JP 2002561459 A JP2002561459 A JP 2002561459A JP 2002561459 A JP2002561459 A JP 2002561459A JP 2004517944 A JP2004517944 A JP 2004517944A
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- pantoprazole
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- 238000000034 method Methods 0.000 title claims abstract description 35
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960005019 pantoprazole Drugs 0.000 title claims abstract description 19
- 239000000543 intermediate Substances 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical group CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 3
- RYGXNMUVOHCPBF-UHFFFAOYSA-N 4-chloro-3-methoxy-2-methylpyridine Chemical compound COC1=C(C)N=CC=C1Cl RYGXNMUVOHCPBF-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 238000006198 methoxylation reaction Methods 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims 3
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims 1
- 239000002798 polar solvent Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002425 crystallisation Methods 0.000 description 11
- -1 benzimidazole compound Chemical class 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- ISRRJUHDGVMYLE-UHFFFAOYSA-N (4-chloro-3-methoxypyridin-2-yl)methanol Chemical compound COC1=C(Cl)C=CN=C1CO ISRRJUHDGVMYLE-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000012264 purified product Substances 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 0 CC(/C=C/N/C=*(\C[N+])/CSc1nc(cc(*)cc2)c2[n]1)=C Chemical compound CC(/C=C/N/C=*(\C[N+])/CSc1nc(cc(*)cc2)c2[n]1)=C 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- KPQDKAMSAVONFC-UHFFFAOYSA-N 4-chloro-2-(chloromethyl)-3-methoxypyridine Chemical compound COC1=C(Cl)C=CN=C1CCl KPQDKAMSAVONFC-UHFFFAOYSA-N 0.000 description 2
- HJMVPNAZPFZXCP-UHFFFAOYSA-N 5-(difluoromethoxy)-1,3-dihydrobenzimidazole-2-thione Chemical compound FC(F)OC1=CC=C2NC(=S)NC2=C1 HJMVPNAZPFZXCP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical class SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 238000006137 acetoxylation reaction Methods 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 239000011609 ammonium molybdate Substances 0.000 description 1
- 229940010552 ammonium molybdate Drugs 0.000 description 1
- 235000018660 ammonium molybdate Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940045348 brown mixture Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
一般式（Ｉ）［式中、Ｘはハロゲン原子であり、ｎ＝０または１］の新規の中間体化合物を使用することにより、活性成分であるパントプラゾールを調製するための新規の方法を記載しており、この際、式中、ｎ＝１である場合には、中間体化合物をメトキシル化し、式中、ｎ＝０である場合には、前記の中間体化合物を初めに酸化させてｎ＝１にし、その後、メトキシル化する。さらに、新規の中間体、それを調製する方法も記載している。A new method for preparing the active ingredient pantoprazole by using a new intermediate compound of the general formula (I) wherein X is a halogen atom and n = 0 or 1 is described. At this time, in the formula, when n = 1, the intermediate compound is methoxylated, and when n = 0, the intermediate compound is first oxidized to n = 1 and then methoxylated. In addition, novel intermediates and methods for preparing them are described.
Description
【０００１】
（発明の分野）
本発明は、パントプラゾール（ｐａｎｔｏｐｒａｚｏｌｅ）を調製する方法、さらに、その際に使用される新規の中間体化合物および前記の中間体化合物を調製する方法に関する。
【０００２】
（従来の技術）
パントプラゾールは、式
【０００３】
【化９】
で示される化学的生成物である５−（ジフルオロメトキシ）−２−［［（３，４−ジメトキシ−２−ピリジニル）メチル］スルフィニル］−１Ｈ−ベンゾイミダゾールの国際的一般名である。
【０００５】
この生成物は、通常はそのナトリウム塩の形で、胃潰瘍の治療で使用される活性成分である。
【０００６】
この生成物は、ヨーロッパ特許出願ＥＰ−Ａ−０１６６２８７号に初めて記載され、これは、パントプラゾールが包含される一般式に該当する生成物を調製するためのいくつかの方法も記載している。パントプラゾールを調製するために正確に適用されたこれらの方法の反応シークエンスを、スキーム１に示す。
【０００７】
【化１０】
スキーム１では、置換基Ｙ、Ｚ、Ｚ’、Ｚ”は、脱離基、例えばハロゲン原子であり、置換基ＭおよびＭ’は、アルカリ金属の原子である。
【０００９】
オーストリア特許ＡＴ−Ｂ−３９４３６８号は、別のルートの合成に基づく他の方法を開示しており、この反応シークエンスを、スキーム２に示す。
【００１０】
【化１１】
しかしながら、この方法は、明白な欠点を有する。それというのも、メチル化が、ピリジンの４位にあるＯＨで生じるだけでなく、ベンゾイミダゾール環の水素に結合している窒素でも生じてしまい、所望の生成物と、得られるベンゾイミダゾール化合物の２種の可能なメチル化異性体、すなわち３−メチル異性体または１−メチル異性体との混合物を生じることがあるためであり、このことは、追加のクロマトグラフィー精製ステップが必要となり、得られる収率が低いことを意味している。
【００１２】
ＰＣＴ出願ＷＯ９７／２９１０３号は、パントプラゾールを調製するための他の方法を開示しており、この反応シークエンスを、スキーム３に示す。
【００１３】
【化１２】
前記から分かるように、パントプラゾールを調製するために、そのうちのいくつかは最近のものである様々な合成手順が提案されているが、このことは、この生成物の調製は、十分に開発されているとはまだみなされてなく、より簡単な技術およびより利用しやすい中間体化合物を用いて、良好な化学的収率でパントプラゾールを調製することを可能にする代替方法を開発する必要性がまだ残っていることのしるしである。
【００１５】
（発明の概要）
本発明の目的は、簡単に得られる中間体化合物のみを必要とするパントプラゾールを調製するための新規の方法である。
【００１６】
さらに、前記の方法で使用される新規の中間体化合物、さらにこのような中間体を調製するための方法も、本発明の目的の一部である。
【００１７】
（発明の説明）
本発明の方法は、一般式（Ｉ）の化合物
【００１８】
【化１３】
［上式中、
Ｘは、ハロゲン原子であり、ｎ＝０または１である］から出発して、
ａ）これを、上式中、ｎ＝１である場合には、メトキシル化剤と反応させるか、
ｂ）これを、上式中、ｎ＝０である場合には、初めに酸化させてｎ＝１にし、その後、メトキシル化剤と反応させて、式（ＩＩ）
【００２０】
【化１４】
のパントプラゾールを得ることを特徴とする。
【００２２】
Ｘは好ましくは、塩素原子である
メトキシル化は、好ましくはナトリウムまたはカリウムのアルカリ金属メトキシドを用いて、またはメタノールとアルカリ水酸化物との混合物を使用して、例えばジメチルホルムアミド、ジメチルアセトアミドおよびジメチルスルホキシドなどの極性の、好ましくは非プロトン性溶媒中で行うことができる。所望の場合には、反応を、テトラキストリフェニルホスフィンパラジウムを用いて完了することもでき、その際、反応温度は室温から８０℃の範囲内に保持する。
【００２３】
置換基Ｘが、ハロゲン原子と同等の他の脱離基に相当する場合、対応する結果が生じることは、当技術分野の専門家には明白であろう。
【００２４】
酸化は、過酸、例えば、過安息香酸の存在下に行うこともできるが、過モリブデン酸または過タングステン酸アンモニウムを過酸化水素と共に使用することが好ましい。例えばメタノールおよび水からなる水性アルコール混合物が、溶媒として適切であり、反応を、０℃から３０℃の範囲の温度で行うことができる。
【００２５】
このメトキシル化は、ピリジン環の４−位に対して選択的であり、ベンゾイミダゾール環の窒素に影響を及ぼさないので、本発明の方法によって、前記のオーストリア特許ＡＴ−Ｂ−３９４３６８の方法に特有の欠点は克服されることを指摘すべきである。これによって、より良好な収率および精製がより簡単な粗製反応生成物を得ることができる。
【００２６】
一般式（Ｉ）
【００２７】
【化１５】
［上式中、Ｘおよびｎは、前記の意味を有する］に対応する化合物は、このような化合物自体が新規であり、本発明の目的の一部であり、特に、式（ＩＩＩ）および（ＩＶ）に対応する化合物を、新規なものとして請求する。
【００２９】
【化１６】
化合物（ＩＶ）は、化合物（ＩＩＩ）を、既に説明した方法と同様の方法を使用して、対応するスルホキシドが得られるまで酸化することにより調製する。
【００３１】
他方で、化合物（ＩＩＩ）は、スキーム５に示されている反応によって調製することができる。
【００３２】
【化１７】
つまり、テトラメチルグアニジン（ＴＭＧＨ）などの塩基の存在下での、クロロメチルピリジン化合物（ＶＩ）とベンゾイミダゾールのメルカプタン誘導体（ＶＩＩ）との反応である。
【００３４】
同様に、クロロメチルピリジン化合物（ＶＩ）は、スキーム６の反応シークエンスによる方法により調製することができる。
【００３５】
【化１８】
この方法では、出発生成物Ｎ−酸化２−メチル−３−メトキシ−４−クロロピリジン（Ｘ）を、無水酢酸と４−ジメチルアミノピリジンとを反応させることによりあらかじめ生じさせておいた式：
【００３７】
【化１９】
の酢酸塩と反応させて、アセトキシル化化合物（ＩＸ）を得る。次いで、このアセトキシル化化合物を水性アルカリ媒体中で加水分解して、カルビノール（ＶＩＩＩ）を得て、これを最終的に、塩化チオニル（ＳＯＣｌ２）とＮ，Ｎ−ジメチルホルムアミド（ＤＭＦ）とを反応させることにより生じさせた式
【００３９】
【化２０】
の反応成分と反応させて、クロロメチルピリジン化合物（ＶＩ）を得る。
【００４１】
化合物（ＶＩ）を調製するための異なるステップを、得られた中間体化合物を単離することなく、好ましくは連続させる（「ワンポット」）。
【００４２】
前記の方法により、簡単かつ効率的に、パントプラゾールを良好な収率で得ることができる。
【００４３】
本発明を、次の実施例で詳述するが、本発明はこれに限定されない。
【００４４】
（実施例）
実施例１−化合物（ＩＸ）の調製
【００４５】
【化２１】
無水酢酸４７．５ｍｌ（０．５０２ｍｏｌ）を４−ジメチルアミノピリジン１．６５ｇ（０．０１３５ｍｏｌ）と混合すると、澄明な黄色の溶液が得られ、これを、６５℃〜７０℃に加熱した。この反応は発熱性なので、冷却することにより、この温度を維持した。Ｎ−酸化２−メチル−３−メトキシ−４−クロロピリジン（Ｘ）２５ｇ（０．１４４１ｍｏｌ）を、約７０分間かけて加えた。添加が終了したら、反応をさらに２時間２０分、６５℃〜７０℃に維持し、この時間の後に、放置して６５℃未満に冷却し、メタノール９０ｍｌを徐々に加えたが、その間、６５℃未満の温度を維持した。生じた反応物を、ロータバップ（ｒｏｔａｖａｐ）中で減圧蒸留して、揮発性成分を除去し、化合物（ＩＸ）を含有する残留物をそのまま、次の反応のために使用した。ＣＨＣｌ３／ＭｅＯＨ（１５：１）で溶離されるシリカゲル６０Ｆ２５４での薄層クロマトグラフィーは、Ｒｆ＝０．８２でシングルスポットを示したが、これは、反応が完了したことのしるしであった。
【００４７】
実施例２−化合物（ＶＩＩＩ）の調製
【００４８】
【化２２】
メタノール１１．５ｍｌおよび水１１．５ｍｌを、化合物（ＩＸ）を含有する実施例１からの粗製残留物に加え、その後、水浴中で温度を２５℃から３０℃に維持しながら、粗製残留物に含有される残留酢酸を、３３％ＮａＯＨ水溶液を加えることにより中和した。残留している酸が中和されたら、３３％ＮａＯＨ水溶液１９ｍｌ（０．２１３６ｍｏｌ）を２０分かけて加えたが、その間、温度を２５℃から３０℃に維持し、添加が終了したら、ｐＨ１１．７〜１１．８での加水分解反応を、２時間３０分間、２５℃から３０℃で維持した。反応が終了したら、３５％ＨＣｌを加えることにより、ｐＨを７．０〜７．５に調節したが、その間、温度は２５℃に維持した。この後、塩化メチレン５０ｍｌを加え、攪拌し、放置した後に、相をデカンテーションした。さらに５回の抽出をそれぞれ塩化メチレン３０ｍｌで実施し、溜めた有機層を無水硫酸ナトリウムで乾燥させ、濾過し、洗浄し、ロータバップ中で減圧蒸発させると、約７３℃の融点を有し、化合物（ＶＩＩＩ）を含有する固体残留物が得られた。ＣＨＣｌ３／ＭｅＯＨ（１５：１）で溶離されるシリカゲル６０Ｆ２５４での薄層クロマトグラフィーは、Ｒｆ＝０．５５でメインスポットを示したが、これは、反応が完了したことのしるしであった。こうして得られた粗製残留物をそのまま、次の反応で使用した。
【００５０】
実施例３−化合物（ＶＩ）の調製
【００５１】
【化２３】
化合物２−ヒドロキシメチル−３−メトキシ−４−クロロピリジン（ＶＩＩＩ）約０．１４２ｍｏｌを含有する実施例２で得られた残留物２４．５ｇをＤＭＦ０．５ｍｌおよび無水塩化メチレン３００ｍｌと混合すると、褐色の溶液が得られ、これを、氷水浴中で０℃〜５℃に冷却した。この後、塩化チオニル１１．５ｍｌ（０．１５８５ｍｏｌ）の無水塩化メチレン５０ｍｌ溶液を２０分かけて加えたが、その間、前記の温度を維持した。添加が終了したら、反応をさらに９０分間０℃から５℃に維持し、次いで、水１２０ｍｌおよび３３％ＮａＯＨをｐＨ５〜６になるまで加えたが、その際、約２９ｍｌのＮａＯＨを必要とした。次いで、相をデカンテーションし、分離した。有機相をさらに水１２０ｍｌで抽出し、溜めた水性層をさらに、塩化メチレン４×２５ｍｌで抽出して、ありうる最も多い量の生成物を回収した。溜めた有機相を無水硫酸ナトリウム上で乾燥させ、濾過し、洗浄し、ロータバップ中で減圧蒸発させると、化合物２−クロロメチル−３−メトキシ−４−クロロピリジン（ＶＩ）を含有する残留物が得られた。ＣＨＣｌ３／ＭｅＯＨ（１５：１）で溶離されるシリカゲル６０Ｆ２５４での薄層クロマトグラフィーは、Ｒｆ＝０．８３でメインスポットを示したが、これは、反応が完了したことのしるしであった。こうして得られた粗製残留物をそのまま、次の反応で使用した。
【００５３】
実施例４−化合物（ＩＩＩ）の調製
【００５４】
【化２４】
化合物２−クロロメチル−３−メトキシ−４−クロロピリジン（ＶＩ）約０．１３６ｍｏｌを含有する実施例３で得られた残留物２６．１１ｇを塩化メチレン３７０ｍｌと混合すると、褐色の溶液が得られ、これに、２０℃〜２５℃で、５−ジフルオロメトキシ−２−メルカプトベンゾイミダゾール（ＶＩＩ）２９．３ｇ（０．１３６ｍｏｌ）およびテトラメチルグアニジン（ＴＭＧＨ）１７．１０ｍｌ（０．１３６ｍｏｌ）を加えた。混合物をこの温度で２時間攪拌し、その後、水４５０ｍｌを加えたが、その際、ｐＨは９．５から１０に維持した。その後、相をデカンテーションし、有機層を１ＮのＮａＯＨ水溶液５×５０ｍｌで、その後、水２×５０ｍｌで洗浄した。有機相を水５０ｍｌで、さらにｐＨを５から６に調節するに十分な量の３０％ＨＣｌで処理した。この後、相をデカンテーションし、有機層を無水硫酸ナトリウム上で乾燥させ、濾過し、洗浄し、ロータバップ中で減圧蒸発させると、化合物（ＩＩＩ）を含有する融点６４℃〜７３℃の固体残留物が得られた。ＣＨＣｌ３／ＭｅＯＨ（１５：１）で溶離されるシリカゲル６０Ｆ２５４での薄層クロマトグラフィーは、Ｒｆ＝０．５２でメインスポットを示した。収率８２％。こうして得られた化合物５−（ジフルオロメトキシ）−２−［［（３−メトキシ−４−塩素−２−ピリジニル）メチル］メルカプト］−１Ｈ−ベンゾイミダゾール（ＩＩＩ）をそのまま、次の反応で使用した。
【００５６】
実施例５−化合物（ＩＶ）の調製
【００５７】
【化２５】
実施例４で得られた化合物（ＩＩＩ）２５．８ｇ（０．０６９４ｍｏｌ）をメタノール８８ｍｌと混合すると、褐色の溶液が得られ、これに、水３．７ｍｌ、モリブデン酸アンモニウム０．９９ｇおよび炭酸ナトリウム０．７８ｇを加えた。この系を０℃〜５℃に冷却し、６０％過酸化水素３．４ｍｌ（０．０７５６ｍｏｌ）を加え、反応混合物を０℃〜５℃に１〜２日間保持し、反応の終点を、ＣＨＣｌ３／ＭｅＯＨ（１５：１）で溶離されるシリカゲル６０Ｆ２５４での薄層クロマトグラフィーにより確認した。
【００５９】
反応の間、ヨウ化カリウム、水およびデンプンを用いて試験することにより、反応媒体中の過酸化水素の存在を制御した。過酸化水素を含有するサンプルに作用すると、黒褐色が生じる。クロマトグラフィー制御が反応の終了を示す前に、このアッセイがマイナスである場合には、さらに過酸化水素を加える。
【００６０】
反応が終了したら、水２６０ｍｌを加え、系を再び０℃〜５℃に冷却し、この温度で混合物を２時間攪拌した。固体沈殿物を濾過し、大量の水で洗浄し、６０℃未満の温度で乾燥させると、融点１３０℃〜１３６℃の５−（ジフルオロメトキシ）−２−［［（３−メトキシ−４−塩素−２−ピリジニル）メチル］スルフィニル］−１Ｈ−ベンゾイミダゾール（ＩＶ）が収率８３．５％で得られた。ＣＨＣｌ３／ＭｅＯＨ（１５：１）で溶離されるシリカゲル６０Ｆ２５４での薄層クロマトグラフィーは、Ｒｆ＝０．５でメインスポットを示した。
【００６１】
所望の場合には次の結晶化方法で、化合物（ＩＶ）を精製することができる：
粗製生成物５ｇをアセトン１６ｍｌに懸濁させ、暗褐色の溶液が得られるまで、沸騰するまで加熱した。この後、こうして得られた溶液を放置して、室温に冷却し、次いで再び、−２０℃に冷却し、この温度で、混合物を攪拌することなく２３時間保持した。この後、固体を濾過し、−２０℃に冷却されたアセトン６×４ｍｌで洗浄した。乾燥させると、生じた白色の固体は２．７３ｇであり、１４２℃の融点を有し、薄層クロマトグラフィーでシングルスポットを有した。ＫＢｒを用いての化合物のＩＲスペクトルは、図１に示す。
【００６２】
濾過の母液および洗浄液を含有するアセトン溶液を、２０ｍｌの容量まで濃縮し、粗製化合物をさらに５ｇ加えた。前記の結晶化プロセスを繰り返すと、前記と同様の特性を有する精製生成物がさらに４．１１ｇ得られた。
【００６３】
先行する結晶化からのアセトン溶液を、１７ｍｌの容量まで濃縮し、粗製化合物をさらに４ｇ加えた。前記の結晶化プロセスを繰り返すと、前記と同様の特性を有する精製生成物がさらに２．９１ｇ得られた。
【００６４】
先行の結晶化からのアセトン溶液を、１５ｍｌの容量まで濃縮し、粗製化合物をさらに４ｇ加えた。前記の結晶化プロセスを繰り返すと、前記と同様の特性を有する精製生成物がさらに３．３ｇ得られた。
【００６５】
先行の結晶化からのアセトン溶液を、１６ｍｌの容量まで濃縮し、粗製化合物をさらに４．３６ｇ加えた。前記の結晶化プロセスを繰り返すと、前記と同様の特性を有する精製生成物がさらに３．６２ｇ得られた。
【００６６】
最後に、先行の結晶化からのアセトン溶液を、１０〜１２ｍｌの容量まで濃縮し、攪拌することなく、−２０℃に２日間保持した。この後、固体を濾過し、−２０℃に冷却されたアセトン５×３ｍｌで洗浄した。乾燥すると、固体は１．２６ｇであり、前記と同様の特性を有した。
【００６７】
全ての結晶化からの全収率は、８０％であった。
【００６８】
実施例６−パントプラゾールの調製
【００６９】
【化２６】
実施例５の結晶化により精製された化合物（ＩＶ）１２．９５ｇ（０．０３３４ｍｏｌ）をＮ，Ｎ−ジメチルアセトアミド３８ｍｌと混合し、その後、カリウムメトキシド７．０３ｇ（０．１００３ｍｏｌ）を加えたが、その間、温度を２０℃から３０℃に保持すると、暗褐色の混合物が得られた。この系を約２５℃に約２３時間保持し、その後、反応が終了したら、酢酸３．８２ｍｌを加えることにより、ｐＨを７に調節した。７５℃以下の内部温度で、Ｎ，Ｎ−ジメチルアセトアミドを減圧除去した。水６５ｍｌおよび塩化メチレン５０ｍｌを、こうして得られた残留物に加え、引き続き、相をデカンテーションした。相をデカンテーションしたら、水性相を、さらに塩化メチレン３×２５ｍｌで抽出し、有機相を溜め、生じた溶液を無水硫酸ナトリウム上で乾燥させ、濾過し、洗浄し、ロータバップ中で減圧蒸発させると、粗製残留物が得られ、これに、水５５ｍｌを加えると、懸濁液が得られた（生成物がこの時点で凝固しない場合には、水をデカンテーションし、さらに水５５ｍｌを加えて、生成物の凝固を妨げる残りのＮ，Ｎ−ジメチルアセトアミドを除去する）。固体を濾過し、乾燥させると、赤褐色の粗製パントプラゾール１１．６１ｇが得られた（収率９０％）。
【００７１】
粗製生成物をメタノール１５０ｍｌに溶かすことにより、こうして得られた粗製生成物を脱色すると、暗褐色の溶液が得られた。活性炭７．５ｇを加えるが、その間、２５℃〜３０℃で４５分間攪拌し続け、その後、炭素を濾去し、濾液を洗浄した。次いで、ロータバップ中、減圧下に、４０℃未満の温度で、メタノールを除去した。固体残留物１０．３３ｇが得られ、これをメチルエチルケトン１４．９ｍｌと混合し、懸濁液を、４５℃に約１０分間加熱し、その後、これを初めは室温に、次いで−２０℃に冷却した。この温度を一晩保持し、その後、固体を濾過し、−２０℃に冷却されたメチルエチルケトン６×５ｍｌで洗浄した。乾燥させると、融点１４０℃〜１４１℃の白色の固体７．７５ｇが得られた。ＣＨＣｌ３／ＭｅＯＨ（１５：１）で溶離されるシリカゲル６０Ｆ２５４での薄層クロマトグラフィーは、Ｒｆ＝０．４１でシングルスポットを示し、ＩＲスペクトルはパントプラゾールのＩＲスペクトルと同一であった。
【００７２】
濾液の母液および洗浄液を含有するケトン溶液を９．７ｍｌに濃縮し、４０℃に加熱し、この温度を約５分間維持し、次いで、初めは室温に、次いで−２０℃に冷却し、この温度を４時間維持した。この時間の終了後に、固体を濾過し、−２０℃に冷却されたメチルエチルケトン４×２ｍｌで洗浄した。乾燥すると、前記のものと同様の特性を有する白色の固体０．４２ｇが得られた。
【００７３】
先行の処理からのケトン溶液を、３．１ｍｌに濃縮し、４０℃に加熱し、この温度を約５分間維持し、次いで、初めは室温に、次いで−２０℃に冷却し、この温度を４時間維持した。この時間の終了後に、固体を濾過し、−２０℃に冷却されたメチルエチルケトン５×３ｍｌで洗浄した。乾燥すると、前記のものと同様の特性を有する白ベージュ色の固体０．４１ｇが得られた。
【００７４】
精製後の全収率は、６７％であった。
【００７５】
白色の固体が望ましい場合には、１回または複数回の洗浄を、酢酸イソプロピルを用いて、次のように実施することができる：メチルエチルケトン処理からのパントプラゾール６．６ｇを、酢酸イソプロピル５０ｍｌに懸濁させた。この系（白色懸濁液）を２５℃で約３０分間攪拌し、次いで、０℃〜５℃に冷却し、この温度で約１５分間攪拌し、次いで、固体を濾過し、酢酸イソプロピル３×１５ｍｌで洗浄した。乾燥させると、純粋な白色の固体６．２６ｇが得られた。
【図面の簡単な説明】
【図１】
ＫＢｒを用いての式（ＩＶ）の化合物のＩＲスペクトルを示している。
【化２７】
(Field of the Invention)
The present invention relates to a process for preparing pantoprazole, furthermore to the novel intermediate compounds used in the process and to a process for preparing said intermediate compounds.
[0002]
(Conventional technology)
Pantoprazole has the formula
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Is the international generic name for 5- (difluoromethoxy) -2-[[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, which is a chemical product represented by
[0005]
This product is the active ingredient used in the treatment of gastric ulcers, usually in the form of its sodium salt.
[0006]
This product is described for the first time in European patent application EP-A-0166287, which also describes several methods for preparing products corresponding to the general formula encompassing pantoprazole. The reaction sequence of these methods, applied exactly to prepare pantoprazole, is shown in Scheme 1.
[0007]
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In Scheme 1, the substituents Y, Z, Z ', Z "are leaving groups, for example halogen atoms, and the substituents M and M' are alkali metal atoms.
[0009]
Austrian Patent AT-B-394368 discloses another method based on the synthesis of another route, the reaction sequence of which is shown in Scheme 2.
[0010]
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However, this method has obvious disadvantages. This is because methylation occurs not only at the OH at the 4-position of pyridine but also at the nitrogen bonded to the hydrogen of the benzimidazole ring, and the desired product and the resulting benzimidazole compound This may result in a mixture with the two possible methylated isomers, ie 3-methyl or 1-methyl isomer, which requires an additional chromatographic purification step and is obtained It means that the yield is low.
[0012]
PCT application WO 97/29103 discloses another method for preparing pantoprazole, the reaction sequence of which is shown in Scheme 3.
[0013]
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As can be seen from the above, various synthetic procedures, some of which are recent, have been proposed for preparing pantoprazole, which indicates that the preparation of this product is well developed. Need to develop alternative methods that allow the preparation of pantoprazole in good chemical yields using simpler techniques and more accessible intermediate compounds that are not yet considered to be Is a sign of what remains.
[0015]
(Summary of the Invention)
The object of the present invention is a novel method for preparing pantoprazole which requires only easily obtainable intermediate compounds.
[0016]
Furthermore, the novel intermediate compounds used in the above-mentioned methods, as well as the methods for preparing such intermediates, are also part of the object of the present invention.
[0017]
(Description of the invention)
The process of the present invention provides compounds of general formula (I)
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[In the above formula,
X is a halogen atom, and n = 0 or 1.]
a) reacting this with a methoxylating agent when n = 1 in the above formula,
b) If n = 0 in the above formula, this is first oxidized to n = 1 and then reacted with a methoxylating agent to obtain a compound of formula (II)
[0020]
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Characterized in that pantoprazole is obtained.
[0022]
X is preferably a chlorine atom, the methoxylation is preferably carried out using an alkali metal methoxide of sodium or potassium, or using a mixture of methanol and an alkali hydroxide, for example dimethylformamide, dimethylacetamide and dimethylsulfoxide. The reaction can be carried out in a polar, preferably aprotic, solvent. If desired, the reaction can be completed with tetrakistriphenylphosphine palladium, while keeping the reaction temperature in the range from room temperature to 80 ° C.
[0023]
It will be apparent to those skilled in the art that the corresponding result will occur if the substituent X corresponds to another leaving group equivalent to a halogen atom.
[0024]
The oxidation can be carried out in the presence of a peracid, for example perbenzoic acid, but it is preferred to use permolybdic acid or ammonium pertungstate together with hydrogen peroxide. An aqueous alcohol mixture consisting of, for example, methanol and water is suitable as solvent, and the reaction can be carried out at a temperature in the range from 0 ° C to 30 ° C.
[0025]
This methoxylation is selective for the 4-position of the pyridine ring and does not affect the nitrogen of the benzimidazole ring, so that the process of the present invention is unique to the process of the aforementioned Austrian patent AT-B-394368. It should be pointed out that the disadvantages of are overcome. This gives a crude reaction product with better yield and easier purification.
[0026]
General formula (I)
[0027]
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Compounds corresponding to the above formulas in which X and n have the meaning given above are such compounds themselves which are novel and are part of the object of the present invention, in particular of the formulas (III) and ( The compounds corresponding to IV) are claimed as new.
[0029]
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Compound (IV) is prepared by oxidizing compound (III) using a method similar to that previously described until the corresponding sulfoxide is obtained.
[0031]
On the other hand, compound (III) can be prepared by the reaction shown in Scheme 5.
[0032]
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That is, the reaction between the chloromethylpyridine compound (VI) and the mercaptan derivative of benzimidazole (VII) in the presence of a base such as tetramethylguanidine (TMGH).
[0034]
Similarly, the chloromethylpyridine compound (VI) can be prepared by a method according to the reaction sequence in Scheme 6.
[0035]
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In this method, the starting product N-oxide 2-methyl-3-methoxy-4-chloropyridine (X) was previously generated by reacting acetic anhydride with 4-dimethylaminopyridine:
[0037]
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To give an acetoxylated compound (IX). Then the acetoxylation compound is hydrolyzed in an aqueous alkaline medium to obtain the carbinol (VIII), which is finally thionyl chloride (SOCl 2) N, and N- dimethylformamide (DMF) Formula generated by reacting
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To give the chloromethylpyridine compound (VI).
[0041]
The different steps for preparing compound (VI) are preferably carried out without isolation of the intermediate compound obtained ("one pot").
[0042]
By the above-mentioned method, pantoprazole can be obtained easily and efficiently with a good yield.
[0043]
The present invention is described in detail in the following examples, but the present invention is not limited thereto.
[0044]
(Example)
Example 1-Preparation of compound (IX)
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Mixing 47.5 ml (0.502 mol) of acetic anhydride with 1.65 g (0.0135 mol) of 4-dimethylaminopyridine resulted in a clear yellow solution, which was heated to 65-70 <0> C. Since the reaction is exothermic, this temperature was maintained by cooling. 25 g (0.1441 mol) of N-oxide 2-methyl-3-methoxy-4-chloropyridine (X) were added over about 70 minutes. When the addition was complete, the reaction was maintained at 65-70 ° C. for an additional 2 hours and 20 minutes, after which time it was allowed to cool to less than 65 ° C. and 90 ml of methanol was added slowly, during which time 65 ° C. A temperature of less than was maintained. The resulting reaction was vacuum distilled in a rotavap to remove volatile components and the residue containing compound (IX) was used as such for the next reaction. Thin layer chromatography on silica gel 60F 254 eluted with CHCl 3 / MeOH (15: 1) showed a single spot at Rf = 0.82, which was an indication that the reaction was complete. .
[0047]
Example 2 Preparation of Compound (VIII)
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11.5 ml of methanol and 11.5 ml of water are added to the crude residue from Example 1 containing the compound (IX), after which the temperature is kept at 25 to 30 ° C. in a water bath to the crude residue. The residual acetic acid contained was neutralized by adding 33% aqueous NaOH. When the remaining acid was neutralized, 19 ml (0.2136 mol) of a 33% aqueous NaOH solution was added over 20 minutes, during which time the temperature was maintained at 25 ° C to 30 ° C. The hydrolysis reaction at 7-11.8 was maintained at 25 ° C. to 30 ° C. for 2 hours 30 minutes. At the end of the reaction, the pH was adjusted to 7.0-7.5 by adding 35% HCl while maintaining the temperature at 25 ° C. Thereafter, 50 ml of methylene chloride was added, and the mixture was stirred and allowed to stand, and then the phase was decanted. Five more extractions were carried out each with 30 ml of methylene chloride, and the pooled organic layers were dried over anhydrous sodium sulphate, filtered, washed and evaporated under reduced pressure in a rotavap to give a compound with a melting point of about 73 ° C. A solid residue containing (VIII) was obtained. Thin layer chromatography on silica gel 60F 254 eluted with CHCl 3 / MeOH (15: 1) showed a main spot at Rf = 0.55, which was an indication that the reaction was complete. . The crude residue thus obtained was used as such in the next reaction.
[0050]
Example 3 Preparation of Compound (VI)
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Mixing 24.5 g of the residue obtained in Example 2 containing about 0.142 mol of the compound 2-hydroxymethyl-3-methoxy-4-chloropyridine (VIII) with 0.5 ml of DMF and 300 ml of anhydrous methylene chloride gives a brown color. A solution of was obtained, which was cooled to 0-5 ° C. in an ice-water bath. Thereafter, a solution of 11.5 ml (0.1585 mol) of thionyl chloride in 50 ml of anhydrous methylene chloride was added over 20 minutes, while maintaining the above-mentioned temperature. When the addition was complete, the reaction was maintained at 0-5 ° C. for a further 90 minutes, then 120 ml of water and 33% NaOH were added until pH 5-6, requiring about 29 ml of NaOH. The phases were then decanted and separated. The organic phase was extracted with a further 120 ml of water and the pooled aqueous layer was further extracted with 4 × 25 ml of methylene chloride to recover the highest possible amount of product. The pooled organic phases are dried over anhydrous sodium sulphate, filtered, washed and evaporated under reduced pressure in a rotavap to give a residue containing the compound 2-chloromethyl-3-methoxy-4-chloropyridine (VI). Obtained. Thin layer chromatography on silica gel 60F 254 eluted with CHCl 3 / MeOH (15: 1) showed a main spot at Rf = 0.83, which was an indication that the reaction was complete. . The crude residue thus obtained was used as such in the next reaction.
[0053]
Example 4 Preparation of Compound (III)
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26.11 g of the residue obtained in Example 3, containing about 0.136 mol of the compound 2-chloromethyl-3-methoxy-4-chloropyridine (VI), are mixed with 370 ml of methylene chloride to give a brown solution. Then, at 20 ° C. to 25 ° C., 29.3 g (0.136 mol) of 5-difluoromethoxy-2-mercaptobenzimidazole (VII) and 17.10 ml (0.136 mol) of tetramethylguanidine (TMGH) were added. . The mixture was stirred at this temperature for 2 hours, after which 450 ml of water were added while maintaining the pH at 9.5 to 10. Thereafter, the phase was decanted and the organic layer was washed with 5 × 50 ml of 1N aqueous NaOH solution and then with 2 × 50 ml of water. The organic phase was treated with 50 ml of water and a sufficient amount of 30% HCl to adjust the pH to 5-6. After this, the phase is decanted and the organic layer is dried over anhydrous sodium sulphate, filtered, washed and evaporated in vacuo in a rotavap to give a solid residue containing compound (III) with a melting point of 64 ° C. to 73 ° C. Thing was obtained. Thin layer chromatography on silica gel 60F 254 eluted with CHCl 3 / MeOH (15: 1) showed a main spot at Rf = 0.52. 82% yield. The thus obtained compound 5- (difluoromethoxy) -2-[[(3-methoxy-4-chlorin-2-pyridinyl) methyl] mercapto] -1H-benzimidazole (III) was used as it is in the next reaction. .
[0056]
Example 5 Preparation of Compound (IV)
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When 25.8 g (0.0694 mol) of the compound (III) obtained in Example 4 was mixed with 88 ml of methanol, a brown solution was obtained, to which 3.7 ml of water, 0.99 g of ammonium molybdate and sodium carbonate were obtained. 0.78 g was added. The system was cooled to 0-5 ° C., 3.4 ml (0.0756 mol) of 60% hydrogen peroxide was added, the reaction mixture was kept at 0-5 ° C. for 1-2 days, and the end point of the reaction was Confirmed by thin layer chromatography on silica gel 60F 254 eluted with 3 / MeOH (15: 1).
[0059]
During the reaction, the presence of hydrogen peroxide in the reaction medium was controlled by testing with potassium iodide, water and starch. When acting on a sample containing hydrogen peroxide, a dark brown color results. If the assay is negative before chromatographic control indicates the end of the reaction, add more hydrogen peroxide.
[0060]
At the end of the reaction, 260 ml of water were added, the system was again cooled to 0-5 ° C. and the mixture was stirred at this temperature for 2 hours. The solid precipitate is filtered, washed with copious amounts of water and dried at a temperature below 60 ° C. to give 5- (difluoromethoxy) -2-[[(3-methoxy-4-chlorine) with a melting point of 130 ° C. to 136 ° C. 2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (IV) was obtained in a yield of 83.5%. Thin layer chromatography on silica gel 60F 254 eluted with CHCl 3 / MeOH (15: 1) showed a main spot at Rf = 0.5.
[0061]
If desired, compound (IV) can be purified by the following crystallization method:
5 g of the crude product were suspended in 16 ml of acetone and heated to boiling until a dark brown solution was obtained. After this, the solution thus obtained was allowed to cool to room temperature and then again to -20 ° C, at which temperature the mixture was kept without stirring for 23 hours. After this, the solid was filtered and washed with 6 × 4 ml of acetone cooled to −20 ° C. Upon drying, the resulting white solid weighed 2.73 g, had a melting point of 142 ° C., and had a single spot by thin layer chromatography. The IR spectrum of the compound using KBr is shown in FIG.
[0062]
The acetone solution containing the mother liquor of the filtration and the washings was concentrated to a volume of 20 ml and an additional 5 g of the crude compound was added. Repeating the crystallization process yielded an additional 4.11 g of purified product with similar properties as above.
[0063]
The acetone solution from the previous crystallization was concentrated to a volume of 17 ml and an additional 4 g of crude compound was added. Repeating the crystallization process yielded an additional 2.91 g of a purified product having the same properties as above.
[0064]
The acetone solution from the previous crystallization was concentrated to a volume of 15 ml and an additional 4 g of crude compound was added. Repeating the above crystallization process yielded an additional 3.3 g of purified product having the same properties as above.
[0065]
The acetone solution from the previous crystallization was concentrated to a volume of 16 ml and an additional 4.36 g of crude compound was added. Repeating the crystallization process yielded an additional 3.62 g of purified product with the same properties as above.
[0066]
Finally, the acetone solution from the previous crystallization was concentrated to a volume of 10-12 ml and kept at -20 <0> C without stirring for 2 days. After this, the solid was filtered and washed with 5 × 3 ml of acetone cooled to −20 ° C. Upon drying, the solid weighed 1.26 g and had the same properties as above.
[0067]
The overall yield from all crystallizations was 80%.
[0068]
Example 6-Preparation of pantoprazole
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12.95 g (0.0334 mol) of the compound (IV) purified by crystallization of Example 5 was mixed with 38 ml of N, N-dimethylacetamide, and then 7.03 g (0.1003 mol) of potassium methoxide was added. However, while maintaining the temperature between 20 ° C. and 30 ° C., a dark brown mixture was obtained. The system was maintained at about 25 ° C. for about 23 hours, after which the pH was adjusted to 7 by adding 3.82 ml of acetic acid when the reaction was completed. At an internal temperature of 75 ° C. or lower, N, N-dimethylacetamide was removed under reduced pressure. 65 ml of water and 50 ml of methylene chloride are added to the residue thus obtained and the phases are subsequently decanted. Once the phases have been decanted, the aqueous phase is extracted with a further 3 × 25 ml of methylene chloride, the organic phases are pooled, the resulting solution is dried over anhydrous sodium sulphate, filtered, washed and evaporated under reduced pressure in a rotavap. , A crude residue was obtained, to which was added 55 ml of water to give a suspension (if the product did not solidify at this point, decant the water and add another 55 ml of water, Remove the remaining N, N-dimethylacetamide that prevents coagulation of the product). The solid was filtered and dried to give 11.61 g of crude red-brown pantoprazole (90% yield).
[0071]
Decolorization of the crude product thus obtained by dissolving the crude product in 150 ml of methanol gave a dark brown solution. 7.5 g of activated carbon are added, during which stirring is continued for 45 minutes at 25 ° C. to 30 ° C., after which the carbon is filtered off and the filtrate is washed. The methanol was then removed in a rotavap under reduced pressure at a temperature below 40 ° C. 10.33 g of a solid residue were obtained, which was mixed with 14.9 ml of methyl ethyl ketone and the suspension was heated to 45 ° C. for about 10 minutes, after which it was cooled first to room temperature and then to −20 ° C. . This temperature was maintained overnight, after which the solid was filtered and washed with 6 × 5 ml of methyl ethyl ketone cooled to −20 ° C. Upon drying, 7.75 g of a white solid having a melting point of 140 ° C. to 141 ° C. was obtained. Thin layer chromatography on silica gel 60F 254 eluted with CHCl 3 / MeOH (15: 1) showed a single spot at Rf = 0.41 and the IR spectrum was identical to that of pantoprazole.
[0072]
The ketone solution containing the mother liquor of the filtrate and the washings was concentrated to 9.7 ml, heated to 40 ° C. and maintained at this temperature for about 5 minutes, then cooled first to room temperature and then to −20 ° C. For 4 hours. At the end of this time, the solid was filtered and washed with 4 × 2 ml of methyl ethyl ketone cooled to −20 ° C. Drying yielded 0.42 g of a white solid having the same properties as above.
[0073]
The ketone solution from the previous treatment was concentrated to 3.1 ml, heated to 40 ° C. and maintained at this temperature for about 5 minutes, then cooled first to room temperature and then to −20 ° C. and brought the temperature to 4 ° C. Time was maintained. At the end of this time, the solid was filtered and washed with 5 × 3 ml of methyl ethyl ketone cooled to −20 ° C. Drying yielded 0.41 g of a white beige solid having the same properties as above.
[0074]
The overall yield after purification was 67%.
[0075]
If a white solid is desired, one or more washes can be performed with isopropyl acetate as follows: 6.6 g of pantoprazole from methyl ethyl ketone treatment are suspended in 50 ml of isopropyl acetate. Turned cloudy. The system (white suspension) is stirred at 25 ° C. for about 30 minutes, then cooled to 0 ° C. to 5 ° C. and stirred at this temperature for about 15 minutes, then the solid is filtered and 3 × 15 ml of isopropyl acetate And washed. Drying gave 6.26 g of a pure white solid.
[Brief description of the drawings]
FIG.
Figure 3 shows the IR spectrum of the compound of formula (IV) using KBr.
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Claims (14)
Ｘは、ハロゲン原子であり、ｎ＝０または１である］から出発して、
ａ）これを、上式中、ｎ＝１である場合には、メトキシル化剤と反応させるか、
ｂ）これを、上式中、ｎ＝０である場合には、初めに酸化させてｎ＝１にし、その後、メトキシル化剤と反応させることを特徴とする、パントプラゾールを調製する方法。Compound of general formula (I)
X is a halogen atom, and n = 0 or 1.]
a) reacting this with a methoxylating agent when n = 1 in the above formula,
b) A process for preparing pantoprazole, characterized in that when n = 0 in the above formula, it is first oxidized to n = 1 and then reacted with a methoxylating agent.
Ｘはハロゲン原子であり、ｎ＝０または１］A compound of the general formula (I).
X is a halogen atom, and n = 0 or 1]
ｂ）ステップａ）で生じた化合物を、アルカリ媒体中で加水分解するステップと、
ｃ）ステップｂ）で生じた化合物と塩化チオニルとをＮ，Ｎ−ジメチルホルムアミドの存在化に反応させるステップとを含む方法により、式（ＶＩ）の化合物を調製することを特徴とする、請求項１２または請求項１３に記載の方法。a) reacting N-oxidized 2-methyl-3-methoxy-4-chloropyridine and acetic anhydride in the presence of 4-dimethylaminopyridine;
b) hydrolyzing the compound obtained in step a) in an alkaline medium;
c) reacting the compound obtained in step b) with thionyl chloride in the presence of N, N-dimethylformamide to prepare a compound of formula (VI). A method according to claim 12 or claim 13.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200002370A ES2185459B1 (en) | 2000-10-02 | 2000-10-02 | PROCEDURE FOR OBTAINING PANTOPRAZOL AND INTERMEDIATE COMPOUNDS FOR THE SAME. |
| PCT/EP2001/011327 WO2002028852A1 (en) | 2000-10-02 | 2001-10-01 | A process for the preparation of pantoprazole and intermediates therefor |
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| JP2004517944A true JP2004517944A (en) | 2004-06-17 |
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| US (1) | US7060839B2 (en) |
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| AT (1) | ATE275561T1 (en) |
| AU (1) | AU2001293856A1 (en) |
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| ES (2) | ES2185459B1 (en) |
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| MX (1) | MXPA03002908A (en) |
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| ES2163372B1 (en) * | 2000-03-13 | 2003-05-01 | Esteve Quimica Sa | OXIDATION PROCEDURE OF A SULFOXIDE TIOETER GROUP. |
| CA2510849A1 (en) | 2002-12-19 | 2004-07-08 | Teva Pharmaceutical Industries Ltd | Solid states of pantoprazole sodium, processes for preparing them and processes for preparing known pantoprazole sodium hydrates |
| US20040235904A1 (en) * | 2003-03-12 | 2004-11-25 | Nina Finkelstein | Crystalline and amorphous solids of pantoprazole and processes for their preparation |
| MXPA05013316A (en) * | 2003-06-10 | 2006-03-17 | Teva Pharma | Process for preparing 2-[(pyridinyl)methyl]sulfinyl-substituted benzimidazoles and novel chlorinated derivatives of pantoprazole. |
| ITMI20031813A1 (en) * | 2003-09-23 | 2005-03-24 | Dinamite Dipharma S P A In Forma A Bbreviata Diph | PROCEDURE FOR THE PREPARATION OF PANTOPRAZOLE AND ITS SALTS. |
| AU2003288703A1 (en) * | 2003-12-05 | 2005-06-24 | Hetero Drugs Limited | A process for the preparation of substitited pyridinylmethylsulfinyl- benzimidazole enantiomers |
| DE112005003147T5 (en) * | 2004-12-16 | 2008-01-17 | Cipla Ltd. | method |
| ES2264362B1 (en) * | 2004-12-22 | 2007-11-01 | Laboratorios Viñas S.A. | "PROCEDURE FOR OBTAINING DERIVATIVES OF 2- (2-PIRIDINILMETILSUFINIL-1H-BENZIMIDAZOLES"). |
| ES2273564B1 (en) * | 2005-03-22 | 2008-04-01 | Quimica Sintetica, S.A. | PROCEDURE FOR THE PREPARATION OF PANTOPRAZOLE. |
| US20100210847A1 (en) * | 2007-07-17 | 2010-08-19 | Ranbaxy Laboratories Limited | Process for the preparation of pantoprazole sodium and pantoprazole sodium sesquihydrate |
| CN103242297A (en) * | 2013-05-20 | 2013-08-14 | 湖北宜恒茶油产业科技有限责任公司 | Preparation method of 5-difluoro methoxyl-2-[[(4-chlorine-3-methoxyl-2-pyridyl)-methyl]sulfo-1H-benzimidazole-hydrate |
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| IL75400A (en) | 1984-06-16 | 1988-10-31 | Byk Gulden Lomberg Chem Fab | Dialkoxypyridine methyl(sulfinyl or sulfonyl)benzimidazoles,processes for the preparation thereof and pharmaceutical compositions containing the same |
| AT394368B (en) * | 1990-08-07 | 1992-03-25 | Byk Gulden Lomberg Chem Fab | Process for the preparation of 3,4-dialkoxypyridines |
| RU2060541C1 (en) | 1992-06-03 | 1996-05-20 | Проектное бюро "ЭЛСАР тоо" | Device for calculation of azimuth correlation function |
| ES2060541B1 (en) * | 1993-02-26 | 1995-11-16 | Vinas Lab | NEW PROCEDURE FOR THE SYNTHESIS OF A DERIVATIVE OF 2- (2-PIRIDILMETILSUFINIL) BENCIMIDAZOLE, AND NEW INTERMEDIATE PRODUCTS OBTAINED WITH THE SAME. |
| ES2166269B1 (en) * | 1999-07-14 | 2003-04-01 | Sint Quimica Sa | NEW PROCEDURE FOR OBTAINING DERIVATIVES OF 2- (2-PIRIDINILMETILSULFINIL) -1H-BENZIMIDAZOL. |
| ES2171116B1 (en) * | 2000-04-14 | 2003-08-01 | Esteve Quimica Sa | PROCEDURE FOR OBTAINING DERIVATIVES OF (((PIRIDIL REPLACED) METAL) UNCLE) BENCIMIDAZOL. |
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| DE60105441D1 (en) | 2004-10-14 |
| ES2185459B1 (en) | 2003-12-16 |
| US7060839B2 (en) | 2006-06-13 |
| WO2002028852A1 (en) | 2002-04-11 |
| TR200402547T4 (en) | 2004-12-21 |
| ES2185459A1 (en) | 2003-04-16 |
| ATE275561T1 (en) | 2004-09-15 |
| DE60105441T2 (en) | 2005-01-20 |
| EP1335913A1 (en) | 2003-08-20 |
| EP1335913B1 (en) | 2004-09-08 |
| US20040049044A1 (en) | 2004-03-11 |
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